EFAXIL

Main information

  • Trade name:
  • EFAXIL Tablets 37.5 Milligram
  • Dosage:
  • 37.5 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EFAXIL Tablets 37.5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0281/136/003
  • Authorization date:
  • 14-08-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Efaxil37.5mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains37.5mgofvenlafaxine(asvenlafaxinehydrochloride).

Forafulllistofexcipientssee6.1.

3PHARMACEUTICALFORM

Tablet

Peachcoloured,roundtablets.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofmajordepressiveepisodes.

Forpreventionofrecurrenceofmajordepressiveepisodes.

4.2Posologyandmethodofadministration

Majordepressiveepisodes

Therecommendedstartingdoseofimmediate-releasevenlafaxineis75mg/dayintwoorthreedivideddosestaken

withfood.Patientsnotrespondingtotheinitial75mg/daydosemaybenefitfromdoseincreasesuptoamaximumdose

of375mg/day.Dosageincreasescanbemadeatintervalsof2weeksormore.Ifclinicallywarrantedduetosymptom

severity,doseincreasescanbemadeatmorefrequentintervals,butnotlessthan4days.

Becauseoftheriskofdose-relatedadverseeffects,doseincrementsshouldbemadeonlyafteraclinicalevaluation(see

section4.4).Thelowesteffectivedoseshouldbemaintained.

Patientsshouldbetreatedforasufficientperiodoftime,usuallyseveralmonthsorlonger.Treatmentshouldbe

reassessedregularlyonacase-by-casebasis.Longer-termtreatmentmayalsobeappropriateforpreventionof

recurrenceofmajordepressiveepisodes(MDE).Inmostofthecases,therecommendeddoseinpreventionof

recurrenceofMDEisthesameastheoneusedduringthecurrentepisode.

Antidepressivemedicinalproductsshouldcontinueforatleastsixmonthsfollowingremission.

Useinelderlypatients

Nospecificdoseadjustmentsofvenlafaxineareconsiderednecessarybasedonpatientagealone.

However,cautionshouldbeexercisedintreatingtheelderly(e.g.,duetothepossibilityofrenalimpairment,the

potentialforchangesinneurotransmittersensitivityandaffinityoccurringwithaging).Thelowesteffectivedose

shouldalwaysbeused,andpatientsshouldbecarefullymonitoredwhenanincreaseinthedoseisrequired.

Useinchildrenandadolescentsundertheageof18years

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Controlledclinicalstudiesinchildrenandadolescentswithmajordepressivedisorderfailedtodemonstrateefficacy

anddonotsupporttheuseofvenlafaxineinthesepatients(seesections4.4and4.8).

Theefficacyandsafetyofvenlafaxineforotherindicationsinchildrenandadolescentsundertheageof18havenot

beenestablished.

Useinpatientswithhepaticimpairment

Inpatientswithmildandmoderatehepaticimpairment,ingenerala50%dosereductionshouldbeconsidered.

However,duetointer-individualvariabilityinclearance,individualisationofdosagemaybedesirable.

Therearelimiteddatainpatientswithseverehepaticimpairment.Cautionisadvised,andadosereductionbymore

than50%shouldbeconsidered.Thepotentialbenefitshouldbeweighedagainsttheriskinthetreatmentofpatients

withseverehepaticimpairment.

Useinpatientswithrenalimpairment

Althoughnochangeindosageisnecessaryforpatientswithglomerularfiltrationrate(GFR)between30-70ml/minute,

cautionisadvised.Forpatientsthatrequirehaemodialysisandinpatientswithsevererenalimpairment(GFR<30

ml/min),thedoseshouldbereducedby50%.Becauseofinter-individualvariabilityinclearanceinthesepatients,

individualisationofdosagemaybedesirable.

Withdrawalsymptomsseenondiscontinuationofvenlafaxine

Abruptdiscontinuationshouldbeavoided.Whenstoppingtreatmentwithvenlafaxine,thedoseshouldbegradually

reducedoveraperiodofatleastonetotwoweeksinordertoreducetheriskofwithdrawalreactions(seesections4.4

and4.8).Ifintolerablesymptomsoccurfollowingadecreaseinthedoseorupondiscontinuationoftreatment,then

resumingthepreviouslyprescribeddosemaybeconsidered.Subsequently,thephysicianmaycontinuedecreasingthe

dose,butatamoregradualrate.

Fororaluse

Itisrecommendedthatvenlafaxineimmediate-releasetabletsbetakenwithfood,atapproximatelythesametimeeach

day.

Patientstreatedwithvenlafaxineimmediate-releasetabletsmaybeswitchedtovenlafaxineprolonged-releasecapsules

atthenearestequivalentdailydosage.Forexample,venlafaxineimmediate-releasetablets37.5mgtwicedailymaybe

switchedtovenlafaxineprolonged-releasecapsules75mgoncedaily.Individualdosageadjustmentsmaybenecessary.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Concomitanttreatmentwithirreversiblemonoamineoxidaseinhibitors(MAOIs)iscontraindicatedduetotheriskof

serotoninsyndromewithsymptomssuchasagitation,tremorandhyperthermia.

Venlafaxinemustnotbeinitiatedforatleast14daysafterdiscontinuationoftreatmentwithanirreversibleMAOI.

Venlafaxinemustbediscontinuedforatleast7daysbeforestartingtreatmentwithanirreversibleMAOI(seesections

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4.4Specialwarningsandprecautionsforuse

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,self-harmandsuicide(suiciderelatedevents).This

riskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormoreof

treatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethatthe

riskofsuicidemayincreaseintheearlystagesofrecovery.

Otherpsychiatricconditionsforwhichvenlafaxineisprescribedcanalsobeassociatedwithanincreasedriskof

suicide-relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesame

precautionsobservedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreating

patientswithotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatment,areknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshould

receivecarefulmonitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressant

drugsinadultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressants

comparedtoplaceboinpatientslessthan25yearsold.

Closesupervisionofpatients,andinparticularthoseathighrisk,shouldaccompanydrugtherapy,especiallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviour,andtoseekmedical

adviceimmediatelyifthesesymptomspresent.

Useinchildrenandadolescentsunder18yearsofage

Efaxilshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.Suicide-related

behaviours(suicideattemptandsuicidalthoughts)andhostility(predominantlyaggression,oppositionalbehaviourand

anger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwithantidepressants

comparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatisneverthelesstaken,thepatient

shouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.Inaddition,long-termsafetydatainchildren

andadolescentsconcerninggrowth,maturationandcognitiveandbehaviouraldevelopmentarelacking.

Serotoninsyndrome

Aswithotherserotonergicagents,serotoninsyndrome,apotentiallylife-threateningcondition,mayoccurwith

venlafaxinetreatment,particularlywithconcomitantuseofotheragents,suchasMAO-inhibitors,thatmayaffectthe

serotonergicneurotransmittersystems(seesections4.3and4.5).

Serotoninsyndromesymptomsmayincludementalstatuschanges(e.g.,agitation,hallucinations,coma),autonomic

instability(e.g.,tachycardia,labilebloodpressure,hyperthermia),neuromuscularaberrations(e.g.,hyperreflexia,

incoordination)and/orgastrointestinalsymptoms(e.g.,nausea,vomiting,diarrhoea).

Narrow-angleglaucoma

Mydriasismayoccurinassociationwithvenlafaxine.Itisrecommendedthatpatientswithraisedintraocularpressure

orpatientsatriskforacutenarrow-angleglaucoma(angle-closureglaucoma)becloselymonitored.

Bloodpressure

Dose-relatedincreasesinbloodpressurehavebeencommonlyreportedwithvenlafaxine.Insomecases,severely

elevatedbloodpressurerequiringimmediatetreatmenthasbeenreportedinpostmarketingexperience.Allpatients

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initiationoftreatment.Bloodpressureshouldbereviewedperiodically,afterinitiationoftreatmentandafterdose

increases.

Cautionshouldbeexercisedinpatientswhoseunderlyingconditionsmightbecompromisedbyincreasesinblood

pressure,e.g.,thosewithimpairedcardiacfunction.

Heartrate

Increasesinheartratecanoccur,particularlywithhigherdoses.Cautionshouldbeexercisedinpatientswhose

underlyingconditionsmightbecompromisedbyincreasesinheartrate.

Cardiacdiseaseandriskofarrhythmia

Venlafaxinehasnotbeenevaluatedinpatientswitharecenthistoryofmyocardialinfarctionorunstableheartdisease.

Therefore,itshouldbeusedwithcautioninthesepatients.

Inpostmarketingexperience,fatalcardiacarrhythmiashavebeenreportedwiththeuseofvenlafaxine,especiallyin

overdose.Thebalanceofrisksandbenefitsshouldbeconsideredbeforeprescribingvenlafaxinetopatientsathighrisk

ofseriouscardiacarrhythmia.

Convulsions

Convulsionsmayoccurwithvenlafaxinetherapy.Aswithallantidepressants,venlafaxineshouldbeintroducedwith

cautioninpatientswithahistoryofconvulsions,andconcernedpatientsshouldbecloselymonitored.Treatmentshould

bediscontinuedinanypatientwhodevelopsseizures.

Hyponatraemia

Casesofhyponatraemiaand/ortheSyndromeofInappropriateAntidiureticHormone(SIADH)secretionmayoccur

withvenlafaxine.Thishasmostfrequentlybeenreportedinvolume-depletedordehydratedpatients.Elderlypatients,

patientstakingdiuretics,andpatientswhoareotherwisevolume-depletedmaybeatgreaterriskforthisevent.

Abnormalbleeding

Medicinalproductsthatinhibitserotoninuptakemayleadtoreducedplateletfunction.Theriskofskinandmucous

membranebleeding,includinggastrointestinalhaemorrhage,maybeincreasedinpatientstakingvenlafaxine.Aswith

otherserotonin-reuptakeinhibitors,venlafaxineshouldbeusedcautiouslyinpatientspredisposedtobleeding,

includingpatientsonanticoagulantsandplateletinhibitors.

Serumcholesterol

Clinicallyrelevantincreasesinserumcholesterolwererecordedin5.3%ofvenlafaxine-treatedpatientsand0.0%of

placebo-treatedpatientstreatedforatleast3monthsinplacebo-controlledclinicaltrials.Measurementofserum

cholesterollevelsshouldbeconsideredduringlong-termtreatment.

Co-administrationwithweightlossagents

Thesafetyandefficacyofvenlafaxinetherapyincombinationwithweightlossagents,includingphentermine,havenot

beenestablished.Co-administrationofvenlafaxineandweightlossagentsisnotrecommended.Venlafaxineisnot

indicatedforweightlossaloneorincombinationwithotherproducts.

Mania/hypomania

Mania/hypomaniamayoccurinasmallproportionofpatientswithmooddisorderswhohavereceivedantidepressants,

includingvenlafaxine.Aswithotherantidepressants,venlafaxineshouldbeusedcautiouslyinpatientswithahistoryor

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Aggression

Aggressionmayoccurinasmallnumberofpatientswhohavereceivedantidepressants,includingvenlafaxine.This

hasbeenreportedunderinitiation,dosechangesanddiscontinuationoftreatment.Aswithotherantidepressants,

venlafaxineshouldbeusedcautiouslyinpatientswithahistoryofaggression.

Discontinuationoftreatment

Withdrawalsymptomswhentreatmentisdiscontinuedarecommon,particularlyifdiscontinuationisabrupt(see

section4.8).Inclinicaltrials,adverseeventsseenontreatmentdiscontinuation(taperingandpost-tapering)occurredin

approximately35%ofpatientstreatedwithvenlafaxineand17%ofpatientstakingplacebo.

Theriskofwithdrawalsymptomsmaybedependentonseveralfactors,includingthedurationanddoseoftherapyand

therateofdosereduction.Dizziness,sensorydisturbances(including

paraesthesia),sleepdisturbances(includinginsomniaandintensedreams),agitationoranxiety,nauseaand/orvomiting,

tremorandheadachearethemostcommonlyreportedreactions.Generally,thesesymptomsaremildtomoderate;

however,insomepatientstheymaybesevereinintensity.Theyusuallyoccurwithinthefirstfewdaysof

discontinuingtreatment,buttherehavebeenveryrarereportsofsuchsymptomsinpatientswhohaveinadvertently

missedadose.Generally,thesesymptomsareself-limitingandusuallyresolvewithin2weeks,thoughinsome

individualstheymaybeprolonged(2-3monthsormore).Itisthereforeadvisedthatvenlafaxineshouldbegradually

taperedwhendiscontinuingtreatmentoveraperiodofseveralweeksormonths,accordingtothepatient’sneeds(see

section4.2).

Akathisia/psychomotorrestlessness

Theuseofvenlafaxinehasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectively

unpleasantordistressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisis

mostlikelytooccurwithinthefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthe

dosemaybedetrimental.

Drymouth

Drymouthisreportedin10%ofpatientstreatedwithvenlafaxine.Thismayincreasetheriskofcaries,andpatients

shouldbeadvisedupontheimportanceofdentalhygiene.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

MonoamineOxidaseInhibitors(MAOI)

Irreversiblenon-selectiveMAOIs

Venlafaxinemustnotbeusedincombinationwithirreversiblenon-selectiveMAOIs.Venlafaxinemustnotbeinitiated

foratleast14daysafterdiscontinuationoftreatmentwithanirreversiblenon-selectiveMAOI.Venlafaxinemustbe

discontinuedforatleast7daysbeforestartingtreatmentwithanirreversiblenon-selectiveMAOI(seesections4.3and

4.4).

Reversible,selectiveMAO-Ainhibitor(moclobemide)

Duetotheriskofserotoninsyndrome,thecombinationofvenlafaxinewithareversibleandselectiveMAOI,suchas

moclobemide,isnotrecommended.FollowingtreatmentwithareversibleMAO-inhibitor,ashorterwithdrawalperiod

than14daysmaybeusedbeforeinitiationofvenlafaxinetreatment.Itisrecommendedthatvenlafaxineshouldbe

discontinuedforatleast7daysbeforestartingtreatmentwithareversibleMAOI(seesection4.4).

Reversible,non-selectiveMAOI(linezolid)

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venlafaxine(seesection4.4).

SevereadversereactionshavebeenreportedinpatientswhohaverecentlybeendiscontinuedfromanMAOIand

startedonvenlafaxine,orhaverecentlyhadvenlafaxinetherapydiscontinuedpriortoinitiationofanMAOI.These

reactionshaveincludedtremor,myoclonus,diaphoresis,nausea,vomiting,flushing,dizziness,andhyperthermiawith

featuresresemblingneurolepticmalignantsyndrome,seizures,anddeath.

Serotoninsyndrome

Aswithotherserotonergicagents,serotoninsyndromemayoccurwithvenlafaxinetreatment,particularlywith

concomitantuseofotheragentsthatmayaffecttheserotonergicneurotransmittersystem(includingtriptans,SSRIs,

SNRIs,lithium,sibutramine,tramadol,orSt.John'sWort[Hypericumperforatum]),withmedicinalagentswhich

impairmetabolismofserotonin(includingMAOIs),orwithserotoninprecursors(suchastryptophansupplements).

IfconcomitanttreatmentofvenlafaxinewithanSSRI,anSNRIoraserotoninreceptoragonist(triptan)isclinically

warranted,carefulobservationofthepatientisadvised,particularlyduringtreatmentinitiationanddoseincreases.The

concomitantuseofvenlafaxinewithserotoninprecursors(suchastryptophansupplements)isnotrecommended(see

section4.4).

CNS-activesubstances

TheriskofusingvenlafaxineincombinationwithotherCNS-activesubstanceshasnotbeensystematicallyevaluated.

Consequently,cautionisadvisedwhenvenlafaxineistakenincombinationwithotherCNS-activesubstances.

Ethanol

Venlafaxinehasbeenshownnottoincreasetheimpairmentofmentalandmotorskillscausedbyethanol.However,as

withallCNS-activesubstances,patientsshouldbeadvisedtoavoidalcoholconsumption.

Effectofothermedicinalproductsonvenlafaxine

Ketoconazole(CYP3A4inhibitor)

ApharmacokineticstudywithketoconazoleinCYP2D6extensive(EM)andpoormetabolisers(PM)resultedinhigher

AUCofvenlafaxine(70%and21%inCYP2D6PMandEMsubjects,respectively)andO-desmethylvenlafaxine(33%

and23%inCYP2D6PMandEMsubjects,respectively)followingadministrationofketoconazole.Concomitantuseof

CYP3A4inhibitors(e.g.,atazanavir,clarithromycin,indinavir,itraconazole,voriconazole,posaconazole,ketoconazole,

nelfinavir,ritonavir,saquinavir,telithromycin)andvenlafaxinemayincreaselevelsofvenlafaxineandO-

desmethylvenlafaxine.Therefore,cautionisadvisedifapatient’stherapyincludesaCYP3A4inhibitorandvenlafaxine

concomitantly.

Effectofvenlafaxineonothermedicinalproducts

Lithium

Serotoninsyndromemayoccurwiththeconcomitantuseofvenlafaxineandlithium(seeSerotoninsyndrome).

Diazepam

Venlafaxinehasnoeffectsonthepharmacokineticsandpharmacodynamicsofdiazepamanditsactivemetabolite,

desmethyldiazepam.DiazepamdoesnotappeartoaffectthepharmacokineticsofeithervenlafaxineorO-

desmethylvenlafaxine.Itisunknownwhetherapharmacokineticand/orpharmacodynamicinteractionwithother

benzodiazepinesexists.

Imipramine

Venlafaxinedidnotaffectthepharmacokineticsofimipramineand2-OH-imipramine.Therewasadose-dependent

increaseof2-OH-desipramineAUCby2.5to4.5-foldwhenvenlafaxine75mgto150mgdailywasadministered.

ImipraminedidnotaffectthepharmacokineticsofvenlafaxineandO-desmethylvenlafaxine.Theclinicalsignificance

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Haloperidol

Apharmacokineticstudywithhaloperidolhasshowna42%decreaseintotaloralclearance,a70%increaseinAUC,

an88%increaseinCmax,butnochangeinhalf-lifeforhaloperidol.Thisshouldbetakenintoaccountinpatients

treatedwithhaloperidolandvenlafaxineconcomitantly.Theclinicalsignificanceofthisinteractionisunknown.

Risperidone

VenlafaxineincreasedtherisperidoneAUCby50%,butdidnotsignificantlyalterthepharmacokineticprofileofthe

totalactivemoiety(risperidoneplus9-hydroxyrisperidone).Theclinicalsignificanceofthisinteractionisunknown.

Metoprolol

Concomitantadministrationofvenlafaxineandmetoprololtohealthyvolunteersinapharmacokineticinteractionstudy

forbothmedicinalproductsresultedinanincreaseofplasmaconcentrationsofmetoprololbyapproximately30-40%

withoutalteringtheplasmaconcentrationsofitsactivemetabolite,-hydroxymetoprolol.Theclinicalrelevanceofthis

findinginhypertensivepatientsisunknown.Metoprololdidnotalterthepharmacokineticprofileofvenlafaxineorits

activemetabolite,O-desmethylvenlafaxine.Cautionshouldbeexercisedwithco-administrationofvenlafaxineand

metoprolol.

Indinavir

Apharmacokineticstudywithindinavirhasshowna28%decreaseinAUCanda36%decreaseinC

forindinavir.

IndinavirdidnotaffectthepharmacokineticsofvenlafaxineandO-desmethylvenlafaxine.Theclinicalsignificanceof

thisinteractionisunknown.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseofvenlafaxineinpregnantwomen.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).Thepotentialriskforhumansisunknown.

Venlafaxinemustonlybeadministeredtopregnantwomeniftheexpectedbenefitsoutweighanypossiblerisk.

Aswithotherserotoninreuptakeinhibitors(SSRIs/SNRIs),discontinuationsymptomsmayoccurinthenewbornsif

venlafaxineisuseduntilorshortlybeforebirth.Somenewbornsexposedtovenlafaxinelateinthethirdtrimesterhave

developedcomplicationsrequiringtube-feeding,respiratorysupportorprolongedhospitalisation.Suchcomplications

canariseimmediatelyupondelivery.

ThefollowingsymptomsmaybeobservedinneonatesifthemotherhasusedanSSRI/SNRIlateinpregnancy:

irritability,tremor,hypotonia,persistentcrying,anddifficultyinsuckingorinsleeping.Thesesymptomsmaybedue

toeitherserotonergiceffectsorexposuresymptoms.Inthemajorityofcases,thesecomplicationsareobserved

immediatelyorwithin24hoursafterpartus.

EpidemiologicaldatahavesuggestedthattheuseofSSRIsinpregnancy,particularlyinlatepregnancy,mayincrease

theriskofpersistentpulmonaryhypertensioninthenewborn(PPHN).Althoughthereisnoevidencefortheassociation

ofPPHNtoSNRItreatment,thispotentialriskcannotberuledoutwithEfaxiltakingintoaccounttherelated

mechanismsofaction(increaseinserotoninconcentrations).

Lactation

Venlafaxineanditsactivemetabolite,O-desmethylvenlafaxine,areexcretedinbreastmilk.Arisktothesucklingchild

cannotbeexcluded.Therefore,adecisiontocontinue/discontinuebreast-feedingortocontinue/discontinuetherapy

withEfaxilshouldbemade,takingintoaccountthebenefitofbreast-feedingtothechildandthebenefitofEfaxil

therapytothewoman.

4.7Effectsonabilitytodriveandusemachines

Anypsychoactivemedicinalproductmayimpairjudgment,thinking,andmotorskills.Therefore,anypatientreceiving

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4.8Undesirableeffects

Themostcommonly(>1/10)reportedadversereactionsinclinicalstudieswerenausea,drymouth,headacheand

sweating(includingnightsweats).

Adversereactionsarelistedbelowbysystemorganclassandfrequency.

Frequenciesaredefinedas:verycommon( ≥1/10),common(≥1/100to<1/10),uncommon(≥1/1,000to<1/100),rare

≥1/10,000to<1/1,000),notknown(cannotbeestimatedfromtheavailabledata).

BodySystem Very

Common Common Uncommon Rare NotKnown

Haematological

/Lymphatic Ecchymosis,

Gastrointestinal

haemorrhage Mucousmembrane

bleeding,Prolonged

bleedingtime,

Thrombocytopaenia

,Blooddyscrasias,

(including

agranulocytosis,

aplasticanaemia,

neutropaeniaand

pancytopaenia)

Metabolic/

Nutritional Serumcholesterol

increased,Weight

loss Weightgain Abnormalliver

functiontests,

Hyponatraemia,

Hepatitis,Syndrome

ofInappropriate

Antidiuretic

HormoneSecretion

(SIADH),Prolactin

increased

Nervous Dry

mouth

(10.0%),

Headache

(30.3%)* Abnormaldreams,

Decreasedlibido,

Dizziness,

Increasedmuscle

tonus

(hypertonia),

Insomnia,

Nervousness,

Paresthesia,

Sedation,Tremor,

Confusion,

Apathy,

Hallucinations,

Myoclonus,

Agitation,

Impaired

coordination

andbalance Akathisia/

Psychomotor

restlessness,

Convulsion,

Manic

reaction Neuroleptic

Malignant

Syndrome(NMS),

Serotonergic

syndrome,

Delirium,

Extrapyramidal

reactions(including

dystoniaand

dyskinaesia),

Tardive

dyskinaesia,

Suicidalideation

andbehaviours**

SpecialSenses Abnormalityof

accommodation,

Mydriasis,Visual

disturbance, Alteredtaste

sensation,

Tinnitus Angle-closure

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Inpooledclinicaltrials,theincidenceofheadachewas30.3%withvenlafaxineversus31.3%withplacebo.

Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringvenlafaxinetherapyorearlyafter

BodySystem Very

Common Common Uncommon Rare NotKnown

Cardiovascular Hypertension,

Vasodilatation

(mostlyhot

flashes/flushes),

Palpitations Postural

hypotension,

Syncope,

Tachycardia Hypotension,QT

prolongation,

Ventricular

fibrillation,

Ventricular

tachycardia

(includingtorsade

depointes)

Respiratory Yawning Pulmonary

eosinophilia

Digestive Nausea

(20.0%) Appetite

decreased

(anorexia),

Constipation,

Vomiting Bruxism,

Diarrhoea Pancreatitis

Skin Sweating

(including

night

sweats)

[12.2%] Rash,Alopecia Erythema

multiforme,Toxic

epidermal

necrolysis,Stevens-

Johnsonsyndrome,

Pruritus,Urticaria

Musculoskeletal Rhabdomyolysis

Urogenital Abnormal

ejaculation/orgas

m(males),

Anorgasmia,

Erectile

dysfunction

(impotence),

Urination

impaired(mostly

hesitancy),

Menstrual

disorders

associatedwith

increasedbleeding

orincreased

irregularbleeding

(e.g.,menorrhagia,

metrorrhagia),

Abnormal

orgasm

(females),

Urinary

retention

Bodyasa

Whole Asthenia(fatigue),

Chills Photosensitivity

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Discontinuationofvenlafaxine(particularlywhenabrupt)commonlyleadstowithdrawalsymptoms.

Dizziness,sensorydisturbances(includingparaethesia),sleepdisturbances(includinginsomniaandintensedreams),

agitationoranxiety,nauseaand/orvomiting,tremor,headacheandflusyndromearethemostcommonlyreported

reactions.Generally,theseeventsaremildtomoderateandareself-limiting;however,insomepatients,theymaybe

severeand/orprolonged.

Itisthereforeadvisedthatwhenvenlafaxinetreatmentisnolongerrequired,gradualdiscontinuationbydosetapering

shouldbecarriedout(seesections4.2and4.4).

Paediatricpatients

Ingeneral,theadversereactionprofileofvenlafaxine(inplacebo-controlledclinicaltrials)inchildrenandadolescents

(ages6to17)wassimilartothatseenforadults.Aswithadults,decreasedappetite,weightloss,increasedblood

pressure,andincreasedserumcholesterolwereobserved(seesection4.4).

Inpaediatricclinicaltrialstheadversereactionsuicidalideationwasobserved.Therewerealsoincreasedreportsof

hostilityand,especiallyinmajordepressivedisorder,self-harm.

Particularly,thefollowingadversereactionswereobservedinpaediatricpatients:abdominalpain,agitation,dyspepsia,

ecchymosis,epistaxis,andmyalgia.

4.9Overdose

Inpostmarketingexperience,overdosewithvenlafaxinewasreportedpredominantlyincombinationwithalcohol

and/orothermedicinalproducts.Themostcommonlyreportedeventsinoverdoseincludetachycardia,changesinlevel

ofconsciousness(rangingfromsomnolencetocoma),mydriasis,convulsion,andvomiting.Otherreportedevents

includeelectrocardiographicchanges(e.g.prolongationofQTinterval,bundlebranchblock,QRSprolongation),

ventriculartachycardia,bradycardia,hypotension,vertigo,anddeath.

Publishedretrospectivestudiesreportthatvenlafaxineoverdosagemaybeassociatedwithanincreasedriskoffatal

outcomescomparedtothatobservedwithSSRIantidepressantproducts,butlowerthanthatfortricyclic

antidepressants.Epidemiologicalstudieshaveshownthatvenlafaxine-treatedpatientshaveahigherburdenofsuicide

riskfactorsthanSSRIpatients.Theextenttowhichthefindingofanincreasedriskoffataloutcomescanbeattributed

tothetoxicityofvenlafaxineinoverdosage,asopposedtosomecharacteristicsofvenlafaxine-treatedpatients,isnot

clear.

Prescriptionsforvenlafaxineshouldbewrittenforthesmallestquantityofthemedicinalproductconsistentwithgood

patientmanagementinordertoreducetheriskofoverdose.

Recommendedtreatment

Generalsupportiveandsymptomaticmeasuresarerecommended;cardiacrhythmandvitalsignsmustbemonitored.

Whenthereisariskofaspiration,inductionofemesisisnotrecommended.Gastriclavagemaybeindicatedif

performedsoonafteringestionorinsymptomaticpatients.Administrationofactivatedcharcoalmayalsolimit

absorptionoftheactivesubstance.Forceddiuresis,dialysis,hemoperfusionandexchangetransfusionareunlikelytobe

ofbenefit.Nospecificantidotesforvenlafaxineareknown.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Otherantidepressants-ATCcode:NO6AX16.

Themechanismofvenlafaxine'santidepressantactioninhumansisbelievedtobeassociatedwithitspotentiationof

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metabolite,O-desmethylvenlafaxine(ODV),areinhibitorsofserotoninandnoradrenalinereuptake.Venlafaxinealso

weaklyinhibitsdopamineuptake.Venlafaxineanditsactivemetabolitereduce-adrenergicresponsivenessafterboth

acute(singledose)andchronicadministration.VenlafaxineandODVareverysimilarwithrespecttotheiroverall

actiononneurotransmitterreuptakeandreceptorbinding.

Venlafaxinehasvirtuallynoaffinityforratbrainmuscarinic,cholinergic,H1-histaminergicor1-adrenergicreceptors

invitro.Pharmacologicalactivityatthesereceptorsmayberelatedtovarioussideeffectsseenwithother

antidepressantmedicinalproducts,suchasanticholinergic,sedativeandcardiovascularsideeffects.

Venlafaxinedoesnotpossessmonoamineoxidase(MAO)inhibitoryactivity.

Invitrostudiesrevealedthatvenlafaxinehasvirtuallynoaffinityforopiateorbenzodiazepinesensitivereceptors.

Majordepressiveepisodes

Theefficacyofvenlafaxineimmediate-releaseasatreatmentformajordepressiveepisodeswasdemonstratedinfive

randomised,double-blind,placebo-controlled,short-termtrialsrangingfrom4to6weeksduration,fordosesupto375

mg/day.Theefficacyofvenlafaxineprolonged-releaseasatreatmentformajordepressiveepisodeswasestablishedin

twoplacebo-controlled,short-termstudiesfor8and12weeksduration,whichincludedadoserangeof75to225

mg/day.

Inonelonger-termstudy,adultoutpatientswhohadrespondedduringan8-weekopentrialonvenlafaxineprolonged-

release(75,150,or225mg)wererandomisedtocontinuationoftheirsamevenlafaxineprolonged-releasedoseorto

placebo,forupto26weeksofobservationforrelapse.

Inasecondlonger-termstudy,theefficacyofvenlafaxineinpreventionofrecurrentdepressiveepisodesfora12-

monthperiodwasestablishedinaplacebo-controlleddouble-blindclinicaltrialinadultoutpatientswithrecurrent

majordepressiveepisodeswhohadrespondedtovenlafaxinetreatment(100to200mg/day,onab.i.d.schedule)onthe

lastepisodeofdepression.

5.2Pharmacokineticproperties

Venlafaxineisextensivelymetabolised,primarilytotheactivemetabolite,O-desmethylvenlafaxine(ODV).Mean±

SDplasmahalf-livesofvenlafaxineandODVare5±2hoursand11±2hours,respectively.Steady-stateconcentrations

ofvenlafaxineandODVareattainedwithin3daysoforalmultiple-dosetherapy.VenlafaxineandODVexhibitlinear

kineticsoverthedoserangeof75mgto450mg/day.

Absorption

Atleast92%ofvenlafaxineisabsorbedfollowingsingleoraldosesofimmediate-releasevenlafaxine.Absolute

bioavailabilityis40%to45%duetopresystemicmetabolism.Afterimmediate-releasevenlafaxineadministration,the

peakplasmaconcentrationsofvenlafaxineandODVoccurin2and3hours,respectively.Followingtheadministration

ofvenlafaxineprolonged-releasecapsules,peakplasmaconcentrationsofvenlafaxineandODVareattainedwithin5.5

hoursand9hours,respectively.Whenequaldailydosesofvenlafaxineareadministeredaseitheranimmediate-release

tabletorprolonged-releasecapsule,theprolonged-releasecapsuleprovidesaslowerrateofabsorption,butthesame

extentofabsorptioncomparedwiththeimmediate-releasetablet.Fooddoesnotaffectthebioavailabilityofvenlafaxine

andODV.

Distribution

VenlafaxineandODVareminimallyboundattherapeuticconcentrationstohumanplasmaproteins(27%and30%,

respectively).Thevolumeofdistributionforvenlafaxineatsteady-stateis4.4±1.6L/kgfollowingintravenous

administration.

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Venlafaxineundergoesextensivehepaticmetabolism.Invitroandinvivostudiesindicatethatvenlafaxineisbio

transformedtoitsmajoractivemetabolite,ODV,byCYP2D6.Invitroandinvivostudiesindicatethatvenlafaxineis

metabolisedtoaminor,lessactivemetabolite,

N-desmethylvenlafaxine,byCYP3A4.Invitroandinvivostudiesindicatethatvenlafaxineisaweakinhibitorof

CYP2D6.VenlafaxinedidnotinhibitCYP1A2,CYP2C9,orCYP3A4.

Elimination

Venlafaxineanditsmetabolitesareexcretedprimarilythroughthekidneys.Approximately87%ofavenlafaxinedose

isrecoveredintheurinewithin48hoursaseitherunchangedvenlafaxine(5%),unconjugatedODV(29%),conjugated

ODV(26%),orotherminorinactivemetabolites(27%).Mean±SDplasmasteady-stateclearancesofvenlafaxineand

ODVare1.3±0.6L/h/kgand0.4±0.2L/h/kg,respectively.

Specialpopulations

Ageandgender

SubjectageandgenderdonotsignificantlyaffectthepharmacokineticsofvenlafaxineandODV.

CYP2D6extensive/poormetabolisers

PlasmaconcentrationsofvenlafaxinearehigherinCYP2D6poormetabolisersthanextensivemetabolisers.Because

thetotalexposure(AUC)ofvenlafaxineandODVissimilarinpoorandextensivemetabolisers,thereisnoneedfor

differentvenlafaxinedosingregimensforthesetwogroups.

Patientswithhepaticimpairment

InChild-PughA(mildlyhepaticallyimpaired)andChild-PughB(moderatelyhepaticallyimpaired)subjects,

venlafaxineandODVhalf-liveswereprolongedcomparedtonormalsubjects.Theoralclearanceofbothvenlafaxine

andODVwasreduced.Alargedegreeofintersubjectvariabilitywasnoted.Therearelimiteddatainpatientswith

severehepaticimpairment(seesection4.2).

Patientswithrenalimpairment

Indialysispatients,venlafaxineeliminationhalf-lifewasprolongedbyabout180%andclearancereducedbyabout

57%comparedtonormalsubjects,whileODVeliminationhalf-lifewasprolongedbyabout142%andclearance

reducedbyabout56%.Dosageadjustmentisnecessaryinpatientswithsevererenalimpairmentandinpatientsthat

requirehaemodialysis(seesection4.2).

5.3Preclinicalsafetydata

Studieswithvenlafaxineinratsandmicerevealednoevidenceofcarcinogenesis.Venlafaxinewasnotmutagenicina

widerangeofinvitroandinvivotests.

Animalstudiesregardingreproductivetoxicityhavefoundinratsadecreaseinpupweight,anincreaseinstillborn

pups,andanincreaseinpupdeathsduringthefirst5daysoflactation.Thecauseofthesedeathsisunknown.These

effectsoccurredat30mg/kg/day,4timesthehumandailydoseof375mgofvenlafaxine(onanmg/kgbasis).Theno-

effectdoseforthesefindingswas1.3timesthehumandose.Thepotentialriskforhumansisunknown.

ReducedfertilitywasobservedinastudyinwhichbothmaleandfemaleratswereexposedtoODV.Thisexposurewas

approximately1to2timesthatofahumanvenlafaxinedoseof375mg/day.Thehumanrelevanceofthisfindingis

unknown.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose

Sodiumstarchglycolate(A)

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Yellowironoxide(E172)

Redironoxide(E172)

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable

6.3ShelfLife

3years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

ThetabletsaresuppliedinopaquewhitePVC/PE/PVDC/Aluminiumblisters.Eachpackcontains7,14,28,30or56

tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocal

requirements.

7MARKETINGAUTHORISATIONHOLDER

PinewoodLaboratoriesLimited

Ballymacarbry

Clonmel

Co.Tipperary

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA281/136/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:14 th

August2009

10DATEOFREVISIONOFTHETEXT

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